Efficient synthetic method for β-Enamino esters catalyzed by Yb(OTf)3 under solvent-free conditions

Article abstract of DOI:10.1071/CH06239

A wide range of ?-enamino esters have been synthesized in moderate to excellent yields by reacting 1,3-dicarbonyl compounds with amines in the presence of catalytic amounts of Yb(OTf)₃ (2 mol%). The reaction proceeds smoothly at ambient temperature under solvent-free conditions. The catalyst can be recovered and reused. CSIRO 2006.

Full text of DOI:10.1071/CH06239

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 921–924
Efficient Synthetic Method for β-Enamino Esters Catalyzed
by Yb(OTf)3 under Solvent-Free Conditions
Ravi Varala,A,B Sreelatha Nuvula,A and Srinivas R. AdapaA
A Indian Institute of Chemical Technology, Hyderabad 500007, India.
B Corresponding author. Email: rvarala_iict@yahoo.co.in
A wide range of β-enamino esters have been synthesized in moderate to excellent yields by reacting 1,3-dicarbonyl
compoundswithaminesinthepresenceofcatalyticamountsof Yb(OTf)3 (2 mol%).Thereactionproceedssmoothly
at ambient temperature under solvent-free conditions. The catalyst can be recovered and reused.
Manuscript received: 8 July 2006.
Final version: 8 October 2006.
R3
R1
The development of facile synthetic methods leading to
R1
R3
R4
O
O
N
R4
β-enamino compounds and their derivatives, without byprod-
ucts, is an active ongoing area of research in synthetic organic
chemistry.[1] β-enamino esters are widely used as a versa-
tile class of intermediates for the synthesis of therapeutic
and biologically active analogues including taxol,[2] anti-
convulsant,[3] anti-inflammatory[4] and antitumour agents,[5]
as well as quinoline antibacterials and antimalarials.[6] Sev-
eral methods have been reported for the preparation of
β-enamino compounds.[7] The direct condensation of 1,3-
dicarbonyl compounds with amines is the most simple
approach.[8] A variety of catalysts such as InBr3,[9] mineral
acids,[10] I2,[10a] p-TSA,[11] BF3·Et2O,[12] CeCl3·7H2O,[13]
NaAuCl4,[14] and Zn(ClO4)·6H2O[15] have been used to
improve product yields. Nevertheless, most of the approaches
currently available are associated with one or more disad-
vantages such as the use of either expensive or less easily
available reagents, harsh reaction conditions, long reaction
times, unsatisfactory yields, low selectivity, toxic solvents,
cumbersome product isolation procedures, and requirement
of excess of reagents. Because there is an emerging impor-
tance of these compounds as intermediates in organic synthe-
sis, there is further scope for the development of convenient,
environmentally benign, high-yielding approaches.
Yb(OTf)3
ϩ
HN
Solvent-free, RT
O
R2
R2
Scheme 1.
Table 1. Screening of several Lewis acids for the condensation of
aniline with ethyl acetoacetate under solvent-free conditionsA
Entry
Catalyst
Time [h]
Yield [%]B
1
2
3
4
5
6
7
8
None
48
12
8
15
6
14
4
24
1
6
3
5
3.5
12
4.5
2
36
75
86
84
78
89
67
60
95
48
82
65
74
78
92
88
Nd(NO3)·6H2O
La(NO3)·6H2O
PrCl3·6H2O
TbCl3·6H2O
SmCl3·6H2O
CuI
CAN
9
Yb(OTf)3
Pd(acac)2
VO(acac)2
Ru(acac)3
Co(acac)3
PdCl2
10
11
12
13
14
15
16
RuCl3·3H2O
During the last decade, rare earth metal triflates have been
found to be unique Lewis acids that are water-tolerant, recy-
clable catalysts and can effectively promote several carbon–
carbon and carbon–heteroatom bond formation reactions.[16]
Another promising synthetic approach to environmentally
friendly chemistry is to either minimize or eliminate the use
of harmful organic solvents.A paradigm shift from using sol-
vents toward solvent-free reactions improves outcomes and
simplifies organic synthesis.[17]
RhCl3
A Conditions: ethyl acetoacetate (1 mmol), aniline (1 mmol), reagent
(2 mol%).
B Yields refer to isolated pure products after column chromatography.
reactions,[18] wepresentourresultspertainingtothesynthesis
of β-enamino ketones and esters (Scheme 1).
Screening of several available reagents allowed us to
shortlist Yb(OTf)3 for the enamination of ethyl aceto-
acetate (1 mmol) and aniline (1 mmol) as model substrates
under solvent-free conditions at room temperature (Table 1).
As a part of our ongoing studies to explore the util-
ity of lanthanide triflates and other reagents, especially for
the carbon–carbon and carbon–heteroatom bond formation
© CSIRO 2006
10.1071/CH06239
0004-9425/06/120921

922
R. Varala, S. Nuvula, and S. R. Adapa
1
Table 2. Examination of functionalized amines with ethyl aceto-
acetate using Yb(OTf)3 as catalyst
products were confirmed by H NMR (δH 7.50–12.80 for
NH). Further, the Z-geometry assignment was achieved by
comparison of the reported chemical shifts of the vinylic
protons of similar Z-enaminones.[9,20,21] Most probably the
reaction proceeds through the activation of the carbonyl
group of the acetyl part by complexation with Yb(iii) ion
followed by nucleophilic addition of amines to the car-
bonyl group, and subsequent enaminone formation by stable
intramolecular hydrogen bonding (Scheme 2).
We then reacted aniline with different acetoacetates such
as methyl acetoacetate (MAA), allyl acetoacetate (AAA),
ethyl 4,4,4-trifluoro acetoacetate (TAA), phenyl acetoacetate
(PAA), ethyl benzoyl acetoacetate (EBAA), and acetyl ace-
tone (AA) to give their corresponding β-enamino products.
The order of reactivity is: EAA > MAA (3.5 h, 92%) > PAA
(4 h, 78%) >AAA (8 h, 70%) >AA (24 h, 7%) > EBAA (no
reaction, 24 h) and TAA (no reaction, 24 h). When acetyl
acetone was used with aliphatic amines, a carbinolamine
derivative precipitate was formed.
Entry
Catalyst
HN
Time [h]
6.0
Yield [%]A
1
2
3
68
85
65
CH3
HN
4.5
HN
HN
HN
HN
O
3.0
88B
92
NH
4
5
6
4.0
2.5
5.5
N
N
CH3
Ph
Ph
58
7
8
9
6.0
10
85
90
75
N
N
HN
HN
COMe
N
Next, we studied the enamination of electronically
divergent functionalized piperazines, chosen in order to
understand the substrate scope and tolerance of the present
methodology usingYb(OTf)3 as the catalyst. Results are sum-
marized in Table 2. The yields are fair in almost all cases
and the corresponding β-enamino esters and the new com-
4.0
HN
HN
N
N
N
N
10
4.5
82
A Yields refer to isolated pure products.
B 2 equiv. EAA used.
1
pounds are sufficiently characterized by IR, H NMR, and
mass spectral studies.
Several structurally and electronically divergent amines
and various β-keto esters were also used for effective conden-
sation to take place with some limitations. Results are shown
in Table 3. The condensation of amines to linear β-keto esters
depended on the steric and electronic properties of both par-
ticipants. In general, aliphatic amines were found to be more
reactive in term of times and product yields compared to the
aromatic amines because of higher nucleophilicity (i.e. cyclo-
hexyl amine, allyl amine, benzyl amine; entries 1–6,Table 3).
Reactivities of the divergent anilines were found to depend on
the electronic nature of the substituents. α-Naphthyl amine
(entry 14, Table 3), on reacting with ethyl acetoacetate, gives
the corresponding enamine product in excellent yield (4 h,
95%). The presence of an electron-withdrawing group on the
benzene ring retarded the progress of reaction even when
stirred for 2 days (entries 17, 18, and 19). Generally, ortho-
substituted anilines require longer reaction times. Optically
active (R)-(+)-α-methyl benzyl amine was converted into
the corresponding β-enamino esters with complete retention
(entry 15, Table 3).
In the case of ethylene diamine (entry 21,Table 3) conden-
sation with EAA, 2 equiv. of β-dicarbonyls were used and the
product was formed with two enamino ester groups. Neither
diphenylamine nor dimethyl amine (entry 20, Table 3) gave
the expected products, even with stirring for 24 h.
In conclusion, we have successfully demonstrated the use
of Yb(OTf)3 as a highly efficient, selective and convenient
Lewis acid catalyst for the preparation of pharmacologi-
cally relevant β-enamino compounds in moderate to excellent
yields. The present protocol has several advantages: mild
reaction conditions (room temperature), small quantity of
As seen in Table 1, the condensation product was achieved in
95% yield in 1 h.
FromTable 1, we can conclude thatYb(OTf)3 (entry 9) was
superior with respect to amount of catalyst, reaction times,
and product yields. In the absence of catalyst, the model reac-
tion was run and only 36% of the product could be isolated
even with stirring for two days. Although reactions also pro-
ceeded with RhCl3, RuCl3·3H2O, and La(NO3)3·6H2O, long
reaction times are typical to achieve comparable results to
those obtained with Yb(OTf)3. We noted that the optimum
condition of 2 mol%Yb(OTf)3 is sufficient to carry the reac-
tion forward. The reaction is sluggish when carried out using
even 0.2–0.5 equiv. of catalyst amounts. In addition, the cat-
alyst can be almost quantitatively recovered by adopting the
procedure of Curini et al.,[19] by the addition of 1 N NaOH
to precipitate the catalyst as the corresponding hydroxide
(Yb(OH)3), filtration, and transformation into triflate salt.
Recycled in this way, the catalyst could be reused several
times without loss of activity. The enamination of aniline
with ethyl acetoacetate as model substrate has been repeated
a minimum of three times with yields of 93, 94, and 94%.
To evaluate the scope and limitations of this catalyst’s
application, various linear β-keto esters such as divergent ace-
toacetates were subjected to a range of primary, secondary,
benzylic, and aromatic amines to give the corresponding
β-enamino esters under standardized reaction parameters.
Results are summarized in Tables 2 and 3. The reaction
was clean and highly diastereoselective; in all reactions the
products were obtained with the Z-geometry stabilized by
intramolecular hydrogen bonding. Structures of the crude

Efficient Method for β-Enamino Esters under Solvent-Free Conditions
923
Table 3. Synthesis of β-enamino esters by condensation of β-keto ester 1 with amine 2 catalyzed by Yb(OTf)3
Entry
R1
R2
Amine
Time [min]
Yield [%]A
95
Entry
1
R1
R2
Amine
Time [min] Yield [%]A
Me
OEt
30
45
92
90
NH2
NH2
14
Me
OEt
240
NH2
2
3
Me
Me
OMe
OEt
15
16
Me
Me
OEt
OEt
360
92
48
NH2
60
86
NH2
1440
NH
4
Me
OMe
60
30
84
94
NH2
NH2
o- 2880
p- 2880
o- 2880
p- 2880
o- 2880
p- 2880
N.R.B
N.R.
N.R.
N.R.
N.R.
N.R.
NH2
17
18
Me
Me
OEt
OEt
COOH
5
6
Me
Me
OEt
NH2
NH2
NH2
OMe
60
90
82
CN
o- 180
7
8
Me
Me
OEt
OEt
NH2
CH3
19
20
Me
Me
OEt
OEt
p- 150
o- 240
88
78
O2N
NH2
Ph2NH/Me2NH
1440
N.R.
OCH3
p- 210
88
58
NH2
H2N
21
22
Me
Me
OEt
OEt
60
78
56
CH3
NH2
CH3
9
Me
OEt
1440
OH
720
H2N
N
10
11
Me
Me
OEt
OEt
600
82
78
NH2
F
NH2
23
24
Me
Me
OEt
OEt
960
28
12
H3C
N
o- 480
NH2
Cl
p- 330
93
92
1200
N
NH2
12
13
Me
Me
OEt
OEt
360
Br
NH2
NH2
270
90
I
A Yields refer to pure isolated products.
B No reaction.
Yb(III)
will be a valid contribution to existing processes in the field
of synthesis of β-enamino compounds.
O
O
O
O
Yb(OTf)3
Experimental
CH3
R
CH3
R
Typical Procedure for Preparation of β-Enamino Esters
Mixtures of β-keto ester (1 mmol), amine (1 mmol), and Yb(OTf)3
(0.02 mmol) were stirred at ambient temperature for appropriate times
(Tables 2 and 3).After completion of the reaction, 1 N NaOH (2 mL) was
added, the white precipitate filtered, and the resulting solution extracted
with Et2O (2 × 2 mL). The organic layers were dried over anhydrous
Na2SO4 and the solvent evaporated and subjected to column chromato-
graphy to afford the desired product. Most of the products are known in
the literature and all new compounds were characterized by IR, 1H NMR
spectroscopy, and mass spectrometry.
H2NRЈ
H
O
NHRЈ
NRЈ
O
CH3
R
CH3
R
Scheme 2.
catalyst, operational and experimental simplicity, environ-
mentally benign solvent-free protocol, and easily recoverable
and reusable catalyst for applicability in large scale synthe-
sis. We believe that this Yb(OTf)3 catalyzed methodology
Ethyl 3-Piperidino-2-butenoate
Table 2, Entry 1: νmax/cm−1 1658, 1605. δH (300 MHz, CDCl3) 1.24
(t, J 6.94, 3H), 1.56–1.62 (m, 6H), 2.40 (s, 3H), 3.24–3.29 (m, 4H), 4.21
(q, J 6.94, 2H), 4.70 (s, 1H). m/z (EI) 197 (M+).

924
R. Varala, S. Nuvula, and S. R. Adapa
Ethyl 3-Morpholino-2-butenoate
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Table 2, Entry 3: νmax/cm−1 1656, 1606. δH (300 MHz, CDCl3) 1.19
(t, J 7.53, 3H), 2.33 (s, 3H), 3.14 (t, J 5.28, 4H), 3.66 (t, J 4.53, 4H)-,
4.02 (q, J 6.79, 2H), 4.69 (s, 1H). m/z (EI) 199 (M+).
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Table 2, Entry 4: νmax/cm−1 1652, 1607. δH (300 MHz, CDCl3) 1.24
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Table 2, Entry 7: νmax/cm−1 1658, 1604. δH (300 MHz, CDCl3) 1.24
(t, J 7.55, 3H), 2.38 (s, 3H), 2.42–2.45 (m, 4H), 3.23–3.26 (m, 4H), 3.49
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Table 2, Entry 10: νmax/cm−1 1660, 1607. δH (300 MHz, CDCl3) 1.25
(t, J 7.03, 3H), 2.46 (s, 3H), 3.37 (t, J 5.47, 4H), 3.86 (t, J 5.47, 4H), 4.08
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Table 3, Entry 1: νmax/cm−1 1655, 1607. δH (300 MHz, CDCl3) 1.24
(t, J 7.1, 3H), 1.89 (m, 10H), 1.93 (s, 3H), 3.29–3.34 (m, 1H), 4.08
(q, J 7.1, 2H), 4.39 (s, 1H), 8.66 (br s, 1H, NH). m/z (EI) 211 (M+).
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Ethyl 3-(Benzylamino)-2-butenoate
Table 3, Entry 3: νmax/cm−1 1654, 1605. δH (300 MHz, CDCl3) 1.25
(t, J 7.1, 3H), 1.89 (s, 3H), 4.11 (q, J 7.1, 2H), 4.42 (d, J 6.4, 2H), 4.56
(s, 1H), 7.22–7.39 (m, 5H), 8.95 (br s, 1H, NH). m/z (EI) 219 (M+).
Ethyl 3-(Allylamino)-2-butenoate
Table 3, Entry 5: νmax/cm−1 1649, 1605. δH (300 MHz, CDCl3) 1.24
(t, J 7.1, 3H), 1.89 (s, 3H), 3.83 (m, 2H), 4.07 (q, J 7.1, 2H), 4.47 (s, 1H),
5.15 (d, J 10.4, 1H), 5.20 (d, J 17.2, 1H), 5.81–5.90 (m, 1H), 8.67 (br s,
1H). m/z (EI) 169 (M+).
Ethyl 3-(1-Naphthylamino)-2-butenoate
Table 3, Entry 14: νmax/cm−1 1652, 1607. δH (300 MHz, CDCl3) 1.33
(t, J 7.55, 3H), 1.87 (s, 3H), 4.19 (q, J 7.55, 2H), 4.75 (s, 1H), 6.69–6.75
(m, 1H), 7.35–7.87 (m, 6H), 10.58 (br s, 1H, NH). m/z (EI) 255 (M+).
Ethyl 3-{[2-(3-Ethoxy-1-methyl-3-oxo-1-propenyl)-
aminoethyl]amino}-2-butenoate
Table 3, Entry 21: νmax/cm−1 1648, 1609. δH (300 MHz, CDCl3) 1.24
(t, J 7.1, 6H), 1.93 (s, 6H), 3.34–3.37 (m, 4H), 4.07 (q, J 7.1, 4H), 4.48
(s, 2H), 8.59 (br s, 2H). m/z (EI) 284 (M+).
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Ethyl 3-[(2-Hydroxyethyl)amino]-2-butenoate
Table 3, Entry 22: νmax/cm−1 3360, 1650, 1607. δH (300 MHz, CDCl3)
1.25 (t, J 7.03, 3H), 1.91 (s, 3H), 3.32 (q, J 5.47, 2H), 3.67 (t, J 5.47,
2H), 4.01 (q, J 7.03, 2H), 4.38 (s, 1H), 8.55 (br s, 2H). m/z (EI) 173
(M+).
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Acknowledgments
R.V. thanks DIICT, Dr J. S. Yadav, and Council of Scientific
Industrial Research (CSIR, India) for financial support. IICT
communication number 060527.
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